The field of the invention relates to vitamin D compounds, and more particularly to 19-nor-Vitamin D analogs and their pharmaceutical uses, and especially seco-A-2,19-dinor-1,25-dihydroxyvitamin D3, its biological activities, and its pharmaceutical uses. This latter compound can also be abbreviated simply as “DA2HE.”
The natural hormone, 1α,25-dihydroxyvitamin D3 and its analog in the ergosterol series (i.e., 1α,25-dihydroxyvitamin D2) are known to be highly potent regulators of calcium homeostasis in animals and humans, and their activity in cellular differentiation has also been established. (See Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987)). Many structural, analogs of these metabolites have been prepared and tested, including 1α-hydroxyvitamin D3, 1α-hydroxyvitamin D2, various side chain homologated vitamins and fluorinated analogs. Some of these compounds exhibit an interesting separation of activities in cell differentiation and calcium regulation. These differences in activity may be useful in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
Another class of vitamin D analogs, i.e., the so called 19-nor-vitamin D compounds, is characterized by the replacement of the A-ring exocyclic methylene group (carbon 19), typical of the vitamin D system, by two hydrogen atoms. Biological testing of such 19-nor-analogs (e.g., 1α,25-dihydroxy-19-nor-vitamin D3) revealed a selective activity profile with high potency in inducing cellular differentiation, and very low calcium mobilizing activity. Thus, these compounds are potentially useful as therapeutic agents for the treatment, of malignancies, or the treatment of various skin disorders. Two different methods of synthesis of such 19-nor-vitamin D analogs have been described. (See Perlman et al., Tetrahedron Lett. 31, 1823 (1990); Perlman et al., Tetrahedron Lett. 32, 7663 (1991); and DeLuca et al., U.S. Pat. No. 5,086,191).
In U.S. Pat. No. 4,666,634, 2β-hydroxy and alkoxy (e.g., ED-71) analogs of 1α,25-dihydroxyvitamin D3 have been described and examined by the Chugai group as potential drugs for osteoporosis and as antitumor agents. (See also Okano et al., Biochem. Biophys. Res. Commun. 163, 1444 (1989)). Other 2-substituted (e.g., with hydroxyalkyl, (ED-120) and fluoroalkyl groups) A-ring analogs of 1α,25-dihydroxyvitamin D3 have also been prepared and tested. (See Miyamoto et al., Chem. Pharm. Bull. 41, 1111 (1993); Nishii et al., Osteoporosis Int. Suppl. 1, 190 (1993); and Posner et al., J. Org. Chem. 59, 7855 (1994), and J. Org. Chem. 60, 4617(1995)).
2-substituted analogs of 1α,25-dihydroxy-19-nor-vitamin D3 have also been synthesized, for example compounds substituted at the 2-position with hydroxy or alkoxy groups, (see DeLuca et al., U.S. Pat. No. 5,536,713), with 2-alkyl groups, (see DeLuca et al. U.S. Pat. No. 5,945,410), and with 2-alkylidene groups, (see DeLuca et al. U.S. Pat. No. 5,843,928). These 2-substituted analogs exhibit interesting and selective activity profiles. All these studies indicate that binding sites on vitamin D receptors can accommodate different substituents at C-2 in the synthesized vitamin D analogs.
In a continuing effort to explore the 19-nor class of pharmacologically important vitamin D compounds, analogs which are characterized by the presence of a methylene substituent at carbon 2 (C-2), a hydroxyl group at carbon 1 (C-1), and a shortened side chain attached at carbon 20 (C-20) have also been synthesized and tested. 1α-hydroxy-2-methylene-19-nor-pregnacalciferol is described in U.S. Pat. No. 6,566,352. 1α-hydroxy-2-methylene-19-nor-homopregnacalciferol is described in U.S. Pat. No. 6,579,861, and 1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferol is described in U.S. Pat. No. 6,627,622. All three of these compounds have relatively high binding activity to vitamin D receptors and relatively high cell differentiation activity. However, these compounds have little if any calcemic activity as compared to 1α,25-dihydroxyvitamin D3. Their biological activities make these compounds excellent candidates for a variety of pharmaceutical uses, as set forth in the '352, '861 and '622 patents.
Analogs of the natural hormone 1α,25-dihydroxyvitamin D3 characterized by the transposition of the A-ring exocyclic methylene group from carbon 10 (C-10) to carbon 2 (C-2) (e.g., 1α,25-dihydroxy-2-methylene-19-nor-vitamin D analogs) have been synthesized and tested. (See Sicinski et al., J. Med. Chem., 41, 4662 (1998); Sicinski et al., Steroids 67, 247 (2002); and DeLuca et al., U.S. Pat. Nos. 5,843,928; 5,936,133 and 6,382,071)). In these studies, it was found that 1α,25-dihydroxy-2-methylene-19-nor-vitamin D analogs are characterized by significant biological potency. In addition, the biological potency of such analogs may be enhanced dramatically where “unnatural” (20S)-configuration is present.